Method of producing hydroxy aluminum disalicylate



Nov. 14, 1967 J. M. HoLBl-:RT ETAL 3,352,893

METHOD 0F PRODUCIING HYDROXY ALUMINUM DISALICYLTE Filed Feb. 13, 196s l en/amm Gross l @FHNW/SYS United States Patent O 3,352,393 METHUD F PRDUCENG HYDRGXY ALUMINUM DISALHCYLAEE James M. Halbert, Lookout Mountain, and leny'amin H.

Gross, Chattanooga, Tenn., assignors to Chattern lrug d; lChernical Company, a corporation of Tennessee itliled Feb. 13, 1963, Ser. No. 258,312 '7 fClaims. (Cl. 26th-4423) The present invention relates to salicylate therapy, to a composition particularly adapted for use in the oral administration of salicylates, and to a method of making the composition.

The antipyretic properties of salicylates have been known for centuries. Salicylic acid itself, however, is quite irritating to skin and mucosa so that it can be only used externally. Various derivatives of this acid, however, have been synthesized for systemic use. These derivatives can be grouped in two large classes, the esters of salicylic acid obtained by the substitution of the hydrogen in the carboxyl group and organic acid esters of salicylic acid in which the carboxyl group of salicylic acid is retained and substitution is made in the hydroxy group. By far the most common derivative of the latter type, of course, is aspirin. This drug, however, has several disadvantages which have been the subject of considerable research. For one, aspirin is quite acidic in reaction and cannot be tolerated by many patients for this reason. For another, the salicylate level in the blood which can be achieved through aspirin therapy cannot be maintained for long periods of time, so that frequent doses are required.

The present invention provides an improved salieylate derivative which does not have the very acidic nature of aspirin and which can maintain a reasonably high level of salicylate in the blood stream for extended periods of time.

The compositions of the present invention are applicable to all types of salicylate therapy. The principal application of these compositions, therefore, is in antipyretic compositions in which they function to lower the body temperature. The compositions also have analgesic action since they are capable of alleviating certain types of pain by virtue of a selective central depressant action. Specifically, the compositions are intended for use to alleviate low intensity pain, particularly headache, myalgia, arthralgia, and other pains of this type. The salicylate compositions of the present invention also have the ability to reduce the pain, irnmobility, swelling and inflammation of the joints in acute rheumatic fever.

An object of the present invention is to provide an improved composition for salicylate therapy which eliminates many of the objectionable features of aspirin, calcium salicylate, sodi-um salicylate, etc.

Still another object of the invention is to provide a composition including the compound hydroxy aluminum disalicylate as its active ingredient for oral administration.

A further object of the invention is to provide an improved method for producing the compound hydroxy aluminum disalicylate economically and in high yield.

A further object of the invention is to provide an improved method for maintaining the salicylate level in the blood stream at therapeutically high levels for prolonged periods of time, and embodying the oral administration of hydroxy aluminum disalicylate.

We have now found that the compound of hydroxy aluminum disalicylate has excellent antipyretic properties and that the oral administration of this material serves to maintain a therapeutically acceptable salicylate level in the blood stream for prolonged periods of time. In this respect, the action of hydroxy aluminum disalicylate is considerably diiierent from that of aspirin which may be hydrolyzed in relatively short periods of time but does not maintain its therapeutic effectiveness for long. What is more, compositions containing hydroxy aluminum disalicylate are considerably less acidic than aspirin and so can be tolerated more easily in the gastrointestinal tract.

Another feature of the present invention resides in an improved method for the manufacture of the compound hydroxy aluminum disalicylate. We have found that substantially quantitative yields of this compound can be produced by reacting a solution containing two molecular proportions of salicylic acid in a mixture of water and an alkanol with one molecular proportion 'of an aluminum alcoholate containing from 2 to 4 carbon atoms per molecule in its alkoxide groups. The reaction is carried out at a temperature such that the exothermic reaction between the alcoholate and the salicylic acid causes the evolution of the alkanol from the reaction mixture. In this type of reaction system, it is, therefore, possible to cause the reaction of the aluminum alcoholate with the salicylic acid While simultaneously hydrolyzing off the intermediate alkoxide produced during the reaction. Specifically, the reaction of salicylic acid with aluminum iso- The substantially quantitative yield of the hydroxy aluminum disalicylate is obtained only through proper control of the reaction conditions. The ingredients should be added in substantially stoichiometric amounts; if the alcoholate is added to more than two equivalents of salicylic acid, the excess salicylic acid appears in the filtrate upon isolation of the salts. lf, on the other hand, the reagents are mixed in equal molar ratios, the product obtained does not appear to be homogeneous and filters with dirliculty. This is probably due to the initial formation of the disalicylate while the concentration of salicylic acid is high and the formation of aluminum hydroxide or hydrated aluminum oxide after the salicylic acid has been consumed.

Furthermore, it is important to use the proper solvent for the system. The best solvent system which we have found is the combination of water and an alkanol containing from 2 to 4 carbon atoms per molecule, the alkanol being present in amounts ranging from about 10 to 60% by volu-me. Even at elevated temperatures, water is not a very good solvent for salicylic acid. Warm alkanols are much better, but the reaction of the aluminum alcoholate with salicylic acid, even in correct Iamounts, in anhydrous alcohol produces a very exothermic reaction and an insoluble product which is probably an aluminum alcoholate disalicylate which does not readily lend itself to subsequent hydrolysis.

The reaction temperatures are controlled by the evaporation or boiling of alcohol from the reaction mixture. The heat evolved appears to be iniiuenced by three factors (l) the temperature of the salicylic acid solution; (2) the temperature of the liquid aluminum alcoholate, and (3) the rate of addition of the alcoholate. The iirst temperature range is limited in that salicylic acid will crystallize if the solution becomes too cool and the alcohol will boil o before the completion of the reaction if the solution becomes too hot. For the system involving salicyclic acid and aluminum isopropoxide, the proper temperature appears to be in the range from to 85 C.

The hydroxy aluminum disalicylate is precipitated promptly under the reaction conditions described to proof hydroxy aluminum disalicylate was made. The material was suspended in 1% tragacanth solution and given orally to male mice by a stomach tube. This investigation showed that the salt is considerably less toxic than salicylic acid.

The hydrolysis curve for the hydroxy aluminum di salicylate is illustrated in the single ligure of the drawing. The medium was U.S.P. simulated gastric juice at a temperature of 38 C. An amount of 975 mgs. of the hydroxy aluminum disalicylate in 450 ml. of simulated gastric juice was employed. Samples tor analysis were withdrawn at i regular time intervals. As indicated by the curve, the compound hydrolyzes rather slowly at iirst, reaching a therapeutically effective level about 2 or 3 hours after the start of hydrolysis, but the effective level is maintained for long periods of time, exceeding 7 hours.

For oral administration of the hydroxy aluminum disalicylate, the compound may be combined with the usual binder materials, such as cornstarch or sugars used in tabletting, the binder constituting from about to 50% f by weight of the composition. A typical unit dosage tablet will contain from about 2 to 6 grains of the hydroxy aluminum disalicylate. lf desired, lubricants such as magnesium stearate can be added to facilitate tabletting.

The following specific examples illustrate the manner in which the hydroxy aluminum disalicylate is prepared.

Example I One pound of salicylic acid was dissolved with slow stirring in a mixture of 1300 ml. of water and 500 ml. of anhydrous isopropyl alcohol at 75 to 78 C. With rapid stirring, 0.74 pound of warm liquid aluminum isopropoxide was added in a period of 5 to 6 minutes. A strong evolution of isopropyl alcohol accompanied this exothermic reaction. After 15 minutes of stirring, the mixture began to thicken and was allowed to stand for 15 to 20 minutes. The slurry, although rather viscous, could be stirred and poured onto a filter. The hydroxy aluminum disalicylate was then isolated by iiltering with.

suction, the precipitate ltering very well and yielding a clear iiltrate. The precipitate was washed with a small amount of isopropyl alcohol. The salt was first dried in air at room temperature and then for a short time in an oven atabout 100 C. The yield was 1.2 pounds. The analysis indicated an aluminum content of 7.99%, and a salicylic acid content of 79.11%.

Example II Twenty-one pounds of salicylic acid were dissolved in a mixture of 7.2 gallons of water and 2.8 gallons of anhydrous isopropyl alcohol in an electrically heated vessel with stirring at 75 C. Liquid aluminum isopropoxide` in an amount of 15.5 pounds was added in a five minute period with more rapid stirring, yand stirring was continued for 15 minutes, whereupon the slurry was allowed to stand for 2O minutes and filtered. The precipitate was washed with a gallon of isopropyl alcohol and dried in an oven at 180 F. for six hours. The yield was 25.5 pounds of hydroxy aluminum disalicylate.

It should be evident that ,various modifications can be. made tothe described embodiments without departing from the scope of the present invention.

We claim as our invention:

1. A method for producing the compound hydroxy aluminum disalicylate which comprises reacting a solution of two molecular proportions of salicylic acid in a mixture of water and an alkanol containing from 2 to 4 carbon atoms per molecule with one molecular proportion of an aluminum alcoholate whose alkoxide groups each contain from 2 to 4 carbon atoms, the amount of water presentbeing in sufliciently large excess to provide for hydrolysis of any intermediate alkoxides produced, the reaction being carried out at a temperature suiciently high so that the exothermic reaction between said alcohoiate and said salicylic acid causes evolution of the alkanol from the reaction mixture, thereby controlling the reacton temperature, and recovering the precipitated hydroxy aluminum disalicylate so produced.

2. A method for producing the compound hydroxy aluminum disalicylate which comprises reacting a solution of two molecular. proportions of salicylic acid in a mixture of water and isopropanol with one molecular proportion of aluminum isopropoxide, the amount of water present being in suiciently large excess-to provide for hydrolysis of any intermediate alkoxides produced, the reaction being carried out at a temperature sufficiently high so that the exothermic reaction between said aluminum isopropoxide and said salicylic acid causes evolution of isopropanol from the reaction mixture, thereby controlling the reaction temperature, and recovering the precipitated hydroxy aluminum disalicylate so produced.

3. A method for producing the compound hydroxy aluminum disalicylate which comprises reacting a solution of two molecular proportions of salicylic acid in a mixture of water and an alkanol containing 2 to 4 carbon atoms per molecule, said mixture containing from 10 to 60% .by volume of the alkanol, with one molecular proportion of an aluminum alcoholate whose alkoxide groups t each contain from 2 to 4 carbon atoms, the amount of water present being in suiciently large excess to provide` for hydrolysis of any intermediate alkoxides produced, the reaction being carried out at a temperature sufficiently high so that the exothermic reacton between said alcoholate and said salicylic acid causes evolution of thevalkanol from the reaction mixture, thereby controlling the reaction temperature, and recovering the precipitated hydroxy aluminum disalicylate so produced.

4. A method for producing the compound hydroxy` aluminum disalicylate which comprises dissolving two molecular proportions ofsalicylic acid in a warm mixture of water and an alkanol containing from 2 to 4 carbon atoms per molecule, adding one molecular proportion of an aluminum alkoxide whose alkoxide groups each contain from 2 to 4 carbon atoms to said mixture while stirring said mixture, the .amount of waterpresent being in suiiiciently large excess to provide for hydrolysis of any intermediate alkoxides produced, and recovering the resulting precipitate.

5. A method for producing the compound Ahydroxy* aluminum disalicylate which comprises dissolving two molecular proportions of salicylic acid in a warm mixture of water and isopropanol, adding one molecular proportion of aluminum isopropoxide to said mixture while stirring said mixture, the amount of water present being in suciently large excess to provide for hydrolysis of any intermediate alkoxides. produced, and iiltering the resulting precipitate.

6. The method for producing the compound hydroxy aluminum disalicylate which comprises dissolving two molecular proportions of salicylic acid in a mixture of water and isopropanol at a temperature in the range from to 85 C., adding one molecular proportion of aluminurn isopropoxide to said mixture with stirring, the amountof water present being in suliiciently large excess lto provide for hydrolysis of any `intermediate alkoxides produced, and recovering the precipitate thus produced.

7. A method vfor producing the compound hydroxy aluminurn disalicylate which comprises dissolving two molecular proportions of salicylic acid in a mixture of water and isopropanol containing from 10 to 60% by volume 0f isopropanol at a temperature in the range from 65 t0 85 C., adding one molecular proportion of aluminum isopropoxide to said mixture with stirring, the amount of Water present being in sufficiently large excess to provide for hydrolysis of any intermediate alkoxides produced, and recovering the precipitate thus produced.

References Cited UNITED STATES PATENTS 2,224,256 12/1940 Doushkess 167-65 2,427,887 l9/ 1947 Wallace 167-65 2,63 6,865 4/ 1953 Kimberlin.

6 12/ 1959 Schenck et al. 11/ 1960 Mitra et al. 260-448 5/1961 Cotty et al. 260-480 1'1/1962 Adams 2'60-480 5/ 1965 Davison 260-448 X FOREIGN PATENTS 2/ 1933 Germany.

10 TOBIAS E. LEVOW, Primary Examiner.

JOSHUA G. LEVI-TT, Examiner. H. M. S. SNEED, E. FRANK, Assistant Examiners. 

1. A METHOD FOR PRODUCING THE COMPOUND HYDROXY ALUMINUM DISALICYLATE WHICH COMPRISES REACTING A SOLUTION OF TWO MOLECULAR PROPORTIONS OF SALICYLIC ACID IN A MIXTURE OF WATER AND AN ALKANOL CONTAINING FROM 2 TO 4 CARBON ATOMS PER MOLECULE WITH ONE MOLECULAR PROPORTION OF AN ALUMINUM ALCOHOLATE WHOSE ALKOXIDE GROUPS EACH CONTAIN FROM 2 TO 4 CARBON ATOMS, THE AMOUNT OF WATER PRESENT BEING IN SUFFICIENTLY LARGE EXCESS TO PROVIDE FOR HYDROLYSIS OF ANY INTERMEDIATE ALKOXIDES PRODUCED, THE REACTION BEING CARRIED OUT AT A TEMPERATURE SUFFICIENTLY HIGH SO THAT THE EXOTHERMIC REACTION BETWEEN SAID ALCOHOLATE AND SAID SALICYLIC ACID CAUSES EVOLUTION OF THE ALKANOL FROM THE REACTION MIXTURE, THEREBY CONTROLLING THE REACTON TEMPERATURE, AND RECOVERING THE PRECIPITATED HYDROXY ALUMINUM DISALICYLATE SO PRODUCED. 